Immunological dysfunction have been widely linked to many neuropsychiatric disorders including obsessive compulsive disorder (OCD), major depression, bipolar disorder, autism, schizophrenia and Alzheimer disease. In addition, results from genome wide association studies suggest that genes whose dysfunction have been implicated in immune dysfunction and/or signaling, contribute to increased risk to the above-mentioned mental disorders. However the basis for the above associations is not clear, which is cause or effect? Do the drugs prescribed for neuropsychiatric disorders affect the immune system? We have identified a mouse where defective microglia, the immune system of the brain, appears causal for a distinct pathological behavior. Further, a bone marrow transplant cures this mouse of its pathological behavior. In this mouse we have directly linked a deficiency in the immune system with pathological behavior. Mice with a mutation in Hoxb8 show unexpected behavior manifested by compulsive grooming and hair removal, similar to human with the OCD-spectrum disorder, trichotillomania. These mice first exhibit compulsive grooming, which turns pathological, resulting in hair removal and lesions at the over groomed sites. There are two principle sources of microglia in mammals, a resident population that is present in the brain early during embryogenesis prior to vascularization, and a second population derived from bone marrow that enters the brain after birth. Hoxb8 exclusively labels the second. Having demonstrated a direct relationship between defective microglia and a behavioral pathology, we are now positioned to determine how microglia affect behavior and most importantly how defective microglia leads to distinct behavioral pathology. One can imagine multiple mechanisms and the causality is likely to be multifaceted. We propose molecular approaches to determine how normal microglia differ from Hoxb8 mutant microglia. Genetic approaches will be used to determine if microglia deficiencies manifest a broader range of behavioral pathologies. Two-photon imaging will be used to examine the behavior of normal and mutant microglial filopodia. Finally, electrophysiological experiments will be used to determine if electrical contacts are made between microglia and neurons and whether these contacts are altered in Hoxb8 mutant mice. Further, if electrochemical contacts between microglia and neurons can be detected, can perturbations of microglia activity induce changes in neuronal activity? Through these multiple broad approaches we hope to provide insight into how non-neuronal cells in the brain, microglia, can so profoundly influence behavior and behavioral pathology. PUBLIC HEALTH RELEVANCE: Microglia affect the brain in a multitude of interactions that are only beginning to surface. The Hoxb8 mutant mouse appears to link a microglial dysfunction to compulsive behavior, providing a unique system to study this linkage. Our proposal will not only be directed at establishing the molecular, cellular and neurophysiological basis for this linkage, but also at generating genetic tools to further explore the broader role of microglia in the normal brain as well as in psychiatric conditions